ART. Switching for toxicity : how and when to switch ? Case Discussion

1. ART. Switchingfortoxicity: how and whentoswitch? Case Discussion Luis Soto-Ramírez, MD Head Molecular Virology Unit Department of Infectious Diseases Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran México City, MEXICO

2. Male 31 years old, MSM referred to you to evaluate treatment switch. Smokes 1 pack a day, for the last 10 years. Weight 93 kg (BMI 29), sedentary. Blood Pressure: 120/85 . FH: Father died at 56 due to MI, had DM type 2. PMH: Diagnosed as HIV in March 2005 No OI, no co-infections (hep B-C) Case JMDA.

3. Case: JMDA ARV treatmenthistory

4. Isthis a perfect ART response? Yes No Itdepends – I need more information Case JMDA. Question 1

5. SGPT / ALT: 81 IU/L (13 – 40) SGOT / AST : 41 IU/L (15 – 48) Triglycerides: 8.67 mmol/l (768 mg/dl). Total Cholesterol: 4.18 mmol/l (162 mg/dl). HDL: 0.620 mmol/l (24 mg/dl). Glucose: 5.44 mmol/l (94 mg/dl). Case JDMA. Otherlabs.

6. Framingham Risk.

7. What would you do? Treat with fibrate Diet, exercise and quit smoking Both Case JMDA. Question 2

8. The patient decrease smoking to half a pack/day, but stopped the fibrate due to severe muscle cramps. Six months thereafter, had lost 4 kg, use Omega 3; his viral load is still undetectable and his lipids are: Triglycerides: 9.50 mmol/l (842 mg/dl). Total Cholesterol: 3.90 mmol/l ( 151 mg/dl). HDL: 0.80 mmol/l (31-mg/dl). Case JDMA. Follow up.

9. Framingham Risk.

10. He isnotwillingtostart a fibrateagain. ShouldweconsidertheTG important? Yes No Depends Case JMDA. Question 3

12. Factors associated with mortality in HIV infected patients with metabolic syndrome

13. Wouldyouswitchtreatmenttodecrease TG and CV risk? Yes No Case JMDA. Question4

14. Retrospective, age-matched study of HIV+ and HIV- veterans with dyslipidemia BL TC or TGs > 200 mg/dL On lipid-lowering therapy > 2 months HIV+ subjects on HAART HIV+ subjects less frequently met NCEP goals after 6 months of treatment for dyslipidemia HIV+ subjects may not be receiving optimal care for dyslipidemia 85% of HIV- received simvastatin vs 23% of HIV+ Difference in usage likely due to interactions b/w simvastatin and PIs HIV+ HIV- Respond to lipid-lowering agents in HIV infected individuals 100 P = .033 80 P = .014 64 60 58 60 Patients Achieving NCEP Goal at 6 Months (%) 43 40 28 25 20 11 11 0 TC TG LDL HDL • Hollowell S, et al. ICAAC 2005. Abstract H-338.

15. Switch Pis to NNRTIs vs lipid lowering agents • Colesterol total a los 12 meses

16. Would you switch? Backbone Third agent Both Case JMDA. Question 5

17. Would you do with the backbone? Continue ABC/3TC Change to TDF/FTC Other Case JMDA. Question6

18. LIPID CHANGES WITH ARV TREATMENT *Effects shown are for ritonavir-boosted drugs †Atazanavir not licensed for unboosted use in the UK or EU Adapted from: 1. Martin A and Emery S. Exp Rev Clin Pharmacol 2009;2:381–389; 2. Fautkenheuer G, et al. J Antimicrob Chemother 2012;67:685–690; 3. Cohen C, et al. Lancet 2011;378:229–237; 4. Mills AM, et al. AIDS 2009;23:1679–1688

19. LipidEffects of PIs Thistablerepresentstheauthor’s judgmentabouttherelativelipideffects of theagentslisted, basedonaccumulated data fromstudiesto date. Differentstudieshavereportedvaryinglipideffects, probablyinfluencedbystage of HIV infection, geographicrepresentation, and othercross-studydifferences. As a result, some individual studiesmayseeminconsistentwiththe ratings in thetable; nevertheless, thistablerepresentstheauthor’s bestattempttoreconcilealltheavailable data. Slide courtesy of Stefan Mauss, MD

20. Wouldyou do switchthethirdagentto? Nevirapine PI/r Raltegravir Maraviroc Case JMDA. Question 7

21. SPIRAL Study: Change (mean) in FastingLipidsthoughWeek 48. Martinez E. et al. AIDS 2010; 24: 1697-1707

22. The patient was switched to TVD/Raltegravir. According to SPIRAL the changes in lipids would be: Case JDMA. Follow up.

23. Switch strategies for virologically suppressed patients(confirmed plasma viral load < 50 c/mL) • Indications: • 1. Switch for toxicity • 2. Switch for prevention of long-term toxicity • 3. Switch for simplification • Principles: • 1. A boosted PI may be switched for simplification, prevention or improvement of metabolic abnormalities or adherence facilitation to unboosted atazanavir, an NNRTI or raltegravir only if full activity of the 2 NRTIs remaining is guaranteed. • 2. Simplification of a complex multidrug regimen in antiretroviral-experienced patients with 1) substitution of drugs difficult to administer (enfuvirtide) and/or with poor activity (NRTI in case of multiple NRTI resistance) and/or poor tolerability and 2) addition of new well-tolerable, simpler and active agent(s). • 3. Bid to qd NRTI switch for simplification, prevention of long-term toxicity. • 4. Intra-class switch if drug-specific related adverse event. • 5. Review the complete ARV history and available resistance test results. • 6. Avoid switching to a drug with a low genetic barrier in the presence of a backbone compromised by the possibility of archived class resistance.

24. Conclusions • The importance of TG elevations in HIV+ individuals should be determined • Switches can be good specially in the long run, but are not the complete solution for dislypidemia • Specific switch guidelines should be created • For dyslipidemia and CV risk • For other metabolic complications • For kidney damage • For bone disease

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